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Phorbol 12-myristate 13-acetate upregulates cyclooxygenase-2 expression in human pulmonary epithelial cells via Ras, Raf-1, ERK, and NF-kappaB, but not p38 MAPK, pathways.
Cell Signal. 2005 Mar; 17(3):299-310.CS

Abstract

In this study, we investigated the signaling pathway involved in cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) release by phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, in human pulmonary epithelial cells (A549). PMA-induced COX-2 expression was attenuated by PKC inhibitors (Go 6976 and Ro 31-8220), a Ras inhibitor (manumycin A), a Raf-1 inhibitor (GW 5074), a MEK inhibitor (PD 098059), and an NF-kappaB inhibitor (PDTC), but not by a tyrosine kinase inhibitor (genistein) or a p38 MAPK inhibitor (SB 203580). PMA also caused the activation of Ras, Raf-1, and ERK1/2. PMA-induced activation of Ras and Raf-1 was inhibited by Ro 31-8220 and manumycin A. PMA-mediated activation of ERK1/2 was inhibited by Ro 31-8220, manumycin A, GW 5074, and PD 098059. Stimulation of cells with PMA caused IkappaBalpha phosphorylation, IkappaBalpha degradation, and the formation of a NF-kappaB-specific DNA-protein complex. The PMA-mediated increase in kappaB-luciferase activity was inhibited by Ro 31-8220, manumycin A, GW5074, PD 098059, and PDTC. Taken together, these results indicate that PMA might activate PKC to elicit activation of the Ras/Raf-1/ERK1/2 pathway, which in turn initiates NF-kappaB activation, and finally induces COX-2 expression and PGE2 release in A549 cells.

Authors+Show Affiliations

Graduate Institute of Biomedical Technology, Taipei Medical University, Taipei, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15567061

Citation

Chang, Ming-Shyan, et al. "Phorbol 12-myristate 13-acetate Upregulates Cyclooxygenase-2 Expression in Human Pulmonary Epithelial Cells Via Ras, Raf-1, ERK, and NF-kappaB, but Not P38 MAPK, Pathways." Cellular Signalling, vol. 17, no. 3, 2005, pp. 299-310.
Chang MS, Chen BC, Yu MT, et al. Phorbol 12-myristate 13-acetate upregulates cyclooxygenase-2 expression in human pulmonary epithelial cells via Ras, Raf-1, ERK, and NF-kappaB, but not p38 MAPK, pathways. Cell Signal. 2005;17(3):299-310.
Chang, M. S., Chen, B. C., Yu, M. T., Sheu, J. R., Chen, T. F., & Lin, C. H. (2005). Phorbol 12-myristate 13-acetate upregulates cyclooxygenase-2 expression in human pulmonary epithelial cells via Ras, Raf-1, ERK, and NF-kappaB, but not p38 MAPK, pathways. Cellular Signalling, 17(3), 299-310.
Chang MS, et al. Phorbol 12-myristate 13-acetate Upregulates Cyclooxygenase-2 Expression in Human Pulmonary Epithelial Cells Via Ras, Raf-1, ERK, and NF-kappaB, but Not P38 MAPK, Pathways. Cell Signal. 2005;17(3):299-310. PubMed PMID: 15567061.
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TY - JOUR T1 - Phorbol 12-myristate 13-acetate upregulates cyclooxygenase-2 expression in human pulmonary epithelial cells via Ras, Raf-1, ERK, and NF-kappaB, but not p38 MAPK, pathways. AU - Chang,Ming-Shyan, AU - Chen,Bing-Chang, AU - Yu,Ming-Tze, AU - Sheu,Joen-Rong, AU - Chen,Tseng-Fu, AU - Lin,Chien-Huang, PY - 2004/05/12/received PY - 2004/07/23/accepted PY - 2004/11/30/pubmed PY - 2005/7/20/medline PY - 2004/11/30/entrez SP - 299 EP - 310 JF - Cellular signalling JO - Cell Signal VL - 17 IS - 3 N2 - In this study, we investigated the signaling pathway involved in cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) release by phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, in human pulmonary epithelial cells (A549). PMA-induced COX-2 expression was attenuated by PKC inhibitors (Go 6976 and Ro 31-8220), a Ras inhibitor (manumycin A), a Raf-1 inhibitor (GW 5074), a MEK inhibitor (PD 098059), and an NF-kappaB inhibitor (PDTC), but not by a tyrosine kinase inhibitor (genistein) or a p38 MAPK inhibitor (SB 203580). PMA also caused the activation of Ras, Raf-1, and ERK1/2. PMA-induced activation of Ras and Raf-1 was inhibited by Ro 31-8220 and manumycin A. PMA-mediated activation of ERK1/2 was inhibited by Ro 31-8220, manumycin A, GW 5074, and PD 098059. Stimulation of cells with PMA caused IkappaBalpha phosphorylation, IkappaBalpha degradation, and the formation of a NF-kappaB-specific DNA-protein complex. The PMA-mediated increase in kappaB-luciferase activity was inhibited by Ro 31-8220, manumycin A, GW5074, PD 098059, and PDTC. Taken together, these results indicate that PMA might activate PKC to elicit activation of the Ras/Raf-1/ERK1/2 pathway, which in turn initiates NF-kappaB activation, and finally induces COX-2 expression and PGE2 release in A549 cells. SN - 0898-6568 UR - https://www.unboundmedicine.com/medline/citation/15567061/Phorbol_12_myristate_13_acetate_upregulates_cyclooxygenase_2_expression_in_human_pulmonary_epithelial_cells_via_Ras_Raf_1_ERK_and_NF_kappaB_but_not_p38_MAPK_pathways_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0898-6568(04)00146-9 DB - PRIME DP - Unbound Medicine ER -